Vancomycin Resistance in Enterococci

Enterococci are Gram-positive, facultatively anaerobic bacteria that constitute an important component of the gastrointestinal microbiota but have also emerged as formidable opportunistic pathogens in healthcare settings. Among clinically relevant species, Enterococcus faecalis and Enterococcus faecium are particularly associated with bloodstream infections, urinary tract infections, wound infections, endocarditis, and other healthcare-associated infections. Their clinical significance is amplified by an exceptional capacity to withstand adverse environmental conditions, acquire antimicrobial-resistance determinants, and persist under selective pressure. Enterococcal infections have become increasingly difficult to manage, particularly when resistance extends to multiple antimicrobial classes.

Vancomycin has historically played a central role in the treatment of infections caused by Gram-positive organisms, including enterococci resistant to several β-lactam antibiotics and aminoglycosides. However, the emergence and dissemination of vancomycin-resistant enterococci (VRE) represent a major challenge to antimicrobial therapy and infection control. Vancomycin resistance is primarily associated with the acquisition of specialized genetic determinants, notably the van gene clusters, which alter the biochemical structure of the peptidoglycan precursors targeted by glycopeptide antibiotics. Instead of binding efficiently to the normal D-alanyl-D-alanine terminus of the cell-wall precursor, vancomycin encounters modified termini such as D-alanyl-D-lactate or D-alanyl-D-serine, substantially reducing its affinity and consequently impairing the drug’s antibacterial activity.

The epidemiology of vancomycin resistance is particularly concerning because resistance determinants can be carried on mobile genetic elements, facilitating their dissemination within and potentially between bacterial populations. The vanA genotype is especially important because it generally confers high-level resistance to vancomycin and can occur in strains with substantial capacity for nosocomial transmission. Other genotypes, including vanB, display distinct resistance phenotypes and regulatory characteristics, underscoring the genetic diversity underlying glycopeptide resistance.

The clinical problem posed by VRE extends beyond resistance to a single antimicrobial agent. Enterococci frequently possess intrinsic or acquired resistance mechanisms against multiple antibiotics, narrowing therapeutic options and complicating empirical treatment. Furthermore, colonized patients can serve as reservoirs for transmission, allowing resistant strains to persist within hospitals and disseminate among vulnerable populations. Investigating these interconnected dimensions is essential for developing effective strategies to detect, contain, and treat VRE infections while limiting further expansion of antimicrobial resistance.

Enterococci as commensals and opportunistic pathogens

Enterococcus (plural: enterococci) comprises a group of Gram-positive, facultatively anaerobic bacteria that commonly inhabit the gastrointestinal tract of humans and numerous animal species. Within the intestinal microbiota, enterococci generally exist as commensal organisms and may persist without producing clinically apparent disease. Their ability to tolerate a broad range of environmental conditions, including variations in temperature, pH, osmotic pressure, and nutrient availability, contributes to their persistence in both the intestinal ecosystem and healthcare environments. Although enterococci are frequently regarded as relatively low-virulence organisms compared with many other bacterial pathogens, their remarkable adaptability allows them to become significant opportunistic pathogens when host defenses are compromised or when normal anatomical barriers are disrupted.

Among the numerous species within the genus, Enterococcus faecalis and Enterococcus faecium are the principal species associated with human disease. E. faecalis is frequently recovered from clinical specimens and has historically accounted for a substantial proportion of enterococcal infections. E. faecium, although also an intestinal commensal, has become increasingly important in healthcare-associated infections because of its pronounced capacity to accumulate antimicrobial-resistance determinants. Both organisms can transition from harmless colonizers to invasive pathogens under favorable circumstances, particularly in hospitalized, elderly, critically ill, or immunocompromised patients.

The clinical spectrum of enterococcal disease is broad. Enterococci may cause urinary tract infections, intra-abdominal and pelvic infections, wound and surgical-site infections, infective endocarditis, and bloodstream infections. Their clinical importance is not determined solely by the frequency of infection but also by their ability to survive antimicrobial exposure and persist in healthcare environments. Colonized patients can represent an important reservoir from which resistant organisms may spread to other patients through healthcare workers, contaminated surfaces, medical equipment, or direct contact. The distinction between colonization and infection is particularly important when interpreting microbiological findings and deciding whether antimicrobial treatment is warranted.

The transition of enterococci from intestinal commensals to healthcare-associated pathogens reflects the interaction between microbial adaptability and clinical selection pressures. Broad-spectrum antibiotic exposure can disrupt competing intestinal flora and create ecological opportunities for resistant enterococci to proliferate. Once established, these organisms may persist for extended periods and subsequently cause invasive disease. This ecological resilience provides an important foundation for understanding why antimicrobial-resistant enterococci remain a persistent challenge in modern healthcare systems.

Vancomycin resistance and the emergence of VRE

Vancomycin is a glycopeptide antimicrobial that has traditionally been an important therapeutic option for serious infections caused by Gram-positive bacteria. Its antibacterial activity depends on interference with bacterial cell-wall synthesis. Vancomycin normally binds to the D-alanyl-D-alanine terminus of peptidoglycan precursors, thereby obstructing the enzymatic reactions required for effective construction and maturation of the bacterial cell wall. This mechanism makes the drug particularly valuable against organisms for which alternative antimicrobial options may be limited. However, the development of vancomycin resistance in enterococci has substantially altered the therapeutic landscape.

Enterococci can acquire genetic mechanisms that modify the molecular target recognized by vancomycin. The best-characterized mechanisms involve van gene clusters that redirect synthesis of the peptidoglycan precursor terminus. In resistant organisms, the conventional D-alanyl-D-alanine target is replaced by an altered structure, most notably D-alanyl-D-lactate or, in some resistance phenotypes, D-alanyl-D-serine. These modifications markedly reduce the binding affinity of vancomycin for its target. Consequently, the antibiotic can no longer effectively disrupt cell-wall assembly at concentrations that would inhibit susceptible enterococci.

The resulting organisms are collectively referred to as VRE. Several acquired vancomycin-resistance genotypes have been described, including vanA, vanB, vanD, vanE, vanG, and vanM. Nevertheless, vanA and vanB are the most epidemiologically important resistance determinants in clinical practice. The vanA phenotype is particularly significant because it generally produces high-level resistance to vancomycin and is commonly associated with resistance to other glycopeptides, including teicoplanin. In contrast, vanB generally confers variable levels of vancomycin resistance while susceptibility to teicoplanin is often retained. These differences have practical implications for laboratory detection, epidemiological investigation, and antimicrobial selection.

The importance of vanA and vanB extends beyond their ability to produce a resistant phenotype. Their genetic organization can facilitate acquisition, maintenance, and dissemination of resistance within bacterial populations. Mobile genetic elements can provide mechanisms through which resistance determinants move between strains and, under suitable circumstances, between bacterial species. This genetic mobility makes vancomycin resistance an ecological and epidemiological problem rather than merely an isolated characteristic of individual bacterial strains.

Clinical and infection-control significance of VRE

VRE infections are strongly associated with healthcare environments, where intensive antibiotic exposure, prolonged hospitalization, invasive procedures, and the concentration of vulnerable patients create favorable conditions for their selection and transmission. Hospitals and other healthcare facilities can therefore function as reservoirs for VRE, particularly when colonized patients remain hospitalized for extended periods. The gastrointestinal tract is an important reservoir, and intestinal colonization may precede subsequent infection or transmission to other individuals.

The consequences of VRE infection can be considerable. Invasive infections, particularly bacteremia and endocarditis, may require prolonged antimicrobial treatment and intensive clinical management. Treatment becomes more complicated when VRE occurs in patients who have already received multiple courses of antibiotics or who harbor organisms resistant to additional antimicrobial classes. Multidrug resistance can transform an otherwise manageable infection into a therapeutic problem requiring careful interpretation of antimicrobial susceptibility results and consideration of agents with activity against resistant enterococci.

This problem illustrates a broader phenomenon in antimicrobial resistance. Similar therapeutic difficulties occur with extended-spectrum β-lactamase (ESBL)-producing and metallo-β-lactamase (MBL)-producing bacteria, as resistance can eliminate several conventional treatment options simultaneously. Clinicians must therefore balance microbiological susceptibility, infection site, disease severity, pharmacokinetic and pharmacodynamic considerations, toxicity, and the potential for further resistance selection. The challenge is especially pronounced when infections involve bloodstream or deep-seated sites, where inadequate antimicrobial exposure can result in treatment failure.

The significance of VRE also lies in its potential for dissemination within healthcare networks. Effective control requires more than treating individual infections. Early recognition of colonization or infection, appropriate laboratory identification, antimicrobial stewardship, environmental hygiene, hand hygiene, and implementation of infection-prevention measures are important components of controlling transmission. Surveillance programs can further assist healthcare institutions in identifying emerging resistance patterns and detecting clusters that may indicate ongoing transmission.

An additional concern is the potential transfer of vancomycin-resistance determinants to other Gram-positive pathogens. The possibility of horizontal acquisition of vancomycin-resistance genes by Staphylococcus aureus has generated particular scientific and clinical concern because S. aureus is already a major cause of healthcare-associated infection, including methicillin-resistant S. aureus (MRSA). Although the emergence of vancomycin-resistant S. aureus remains uncommon, the biological possibility of resistance-gene transfer demonstrates why VRE should be regarded as a broader antimicrobial-resistance threat rather than simply a problem confined to enterococci.

Laboratory detection and recognition of VRE

Accurate laboratory recognition of VRE is essential for both patient management and infection-control programs. Routine identification of enterococci to the species level provides an important starting point, but phenotypic antimicrobial susceptibility testing and, where appropriate, molecular detection of resistance determinants may be required to establish vancomycin resistance. Correct differentiation of susceptible and resistant isolates is particularly important because failure to recognize VRE can result in inappropriate antimicrobial therapy and unrecognized transmission within healthcare facilities.

Selective and differential culture media provide a practical approach for screening patients who may be colonized with VRE. Chromogenic media such as Brilliance VRE agar are designed to facilitate the selective recovery and visual differentiation of VRE from clinical specimens (Figure 1). Such media can be used for screening fecal specimens and rectal or other relevant swabs, depending on the laboratory’s validated protocol. The chromogenic reaction assists in the recognition of presumptive VRE colonies, thereby reducing the time and labor associated with conventional screening approaches. Results may be available within approximately 24 hours under appropriate laboratory conditions, although presumptive colonies generally require confirmation using the laboratory’s established identification and susceptibility-testing procedures.

Laboratory detection should therefore be viewed as an integrated process rather than reliance on a single culture plate. Presumptive colonies obtained from selective chromogenic media can undergo species identification followed by antimicrobial susceptibility testing and, when clinically or epidemiologically indicated, molecular characterization of vanresistance determinants. Molecular methods can provide additional information concerning the genetic basis of resistance and may be particularly valuable during outbreaks or epidemiological investigations.

The early recognition of VRE has implications that extend beyond the individual patient. A laboratory result can trigger infection-prevention measures, guide antimicrobial selection, and contribute to institutional surveillance of resistance trends. In this context, microbiology laboratories occupy a critical position at the interface between diagnosis, antimicrobial stewardship, and infection control. Continued refinement of culture-based, phenotypic, and molecular approaches is therefore essential for timely identification of VRE and for limiting the establishment and dissemination of vancomycin resistance in healthcare settings.

Treatment, control and prevention of VRE infections

Management of VRE requires an integrated approach combining appropriate antimicrobial therapy, infection-control practices, and antimicrobial stewardship. Treatment should be guided by the site and severity of infection, the species involved, and the antimicrobial susceptibility profile of the isolate. Colonization with VRE bacteria does not usually require antimicrobial treatment. Therapy is reserved for patients with clinically significant infection. Because VRE frequently exhibit resistance to multiple antimicrobial classes, treatment options may be considerably narrower than those available for susceptible enterococcal infections. Depending on the clinical circumstances and susceptibility results, agents such as linezolid or daptomycin may be considered for serious VRE infections, while other drugs may have a role in selected infections. The choice of therapy should be individualized and supported by susceptibility testing and appropriate pharmacological considerations.

Control of VRE depends heavily on preventing transmission within healthcare facilities. Early laboratory identification of VRE is important because recognition of colonized or infected patients allows infection-prevention measures to be implemented promptly. Hand hygiene remains a fundamental intervention, particularly before and after patient contact. Contact precautions may be implemented according to institutional policies, especially for patients with VRE infection or colonization in high-risk healthcare settings. Dedicated or appropriately disinfected equipment should be used where feasible, and frequently touched environmental surfaces require effective cleaning and disinfection because enterococci can persist in the healthcare environment.

Prevention also depends on reducing unnecessary antimicrobial exposure. Excessive or inappropriate use of broad-spectrum antibiotics can create selective pressure that favors resistant enterococci and facilitates intestinal colonization. Robust antimicrobial stewardship programs therefore play an important preventive role by promoting appropriate drug selection, dosing, duration, and de-escalation when microbiological information becomes available. Surveillance for VRE, screening of high-risk patients where indicated, rapid communication of laboratory results, and investigation of suspected outbreaks further strengthen institutional control measures.

Effective VRE prevention requires coordination between clinicians, microbiologists, pharmacists, nurses, infection-prevention teams, patients, and healthcare-support staff. Combining prudent antimicrobial use with reliable laboratory detection, environmental hygiene, and rigorous transmission-based precautions offers the most sustainable strategy for limiting the clinical and epidemiological impact of VRE.

Further reading

Clinical and Laboratory Standards Institute. (2026). Breakpoint implementation toolkit (BIT). clsi.org/resources/breakpoint-implementation-toolkit/

European Committee on Antimicrobial Susceptibility Testing. (2026). EUCAST. www.eucast.org/

Levitus, M., Rewane, A., & Perera, T. B. (2023). Vancomycin-resistant enterococci. In StatPearls. StatPearls Publishing. www.ncbi.nlm.nih.gov/books/NBK513233/

Miller, W. R., Murray, B. E., Rice, L. B., & Arias, C. A. (2020). Resistance in vancomycin-resistant enterococci. Infectious Disease Clinics of North America, 34(4), 751–771.

Mareković, I., Markanović, M., Lešin, J., & Ćorić, M. (2024). Vancomycin-resistant enterococci: Current understandings of resistance in relation to transmission and preventive strategies. Pathogens, 13(11), 966.

Schröder, C., Beleites, C., Assmann, C., et al. (2015). Detection of vancomycin resistances in enterococci within 3 ½ hours. Scientific Reports, 5, 8217. 

Werner G, Coque T.M, Hammerum A. M et al. (2008). Emergence and spread of vancomycin resistance among enterococci in Europe. Eurosurveillance, 13(47).